1. Pathogenesis of Leishmaniasis
AL – Abbasi A.M.
PhD, FRCP, DCN, DTM&H.
Professor of Infectious Diseases & Clinical immunology,
Baghdad College of Medicine

2. Cinderella Of
Tropical
Medicine

3. Vector – borne zoonosis Emerging disease in relation to the HIV
Overview
Various clinical syndromes caused by obligate intracellular protozoa of genus Leishmania
Vector – borne zoonosis
Emerging disease in relation to the HIV

4. Major Leishmania species causing diseases in humans
Subgenus Leishmania
Clinical syndromes
L. donovani complex:
L. donovani
VL (PKDL, OWCL)
L. infantum
VL (OWCL)
L. chagasi
VL (NWCL)
L. Mexicana Complex:
L. mexicana
NWCL (DCL)
L. amazonensis
NWCL (ML, DCL, VL)
L. tropica
OWCL (VL)
Viscerotropic & Leish. recidivans
L. major
OWCL
L. aethiopica
OWCL (DCL)

5. Subgenus Viannia
L.(V.) braziliensis
NWCL (ML)
L.(V.) guyanensis
L.(V.) panamensis
L.(V.) peruviana
NWCL uta

6. Morphological are less valid Monoclonal antibody specificity.
Classification:
Geographical,
Clinical,
Epidemiological &
Morphological are less valid
PCR, biochemical means
(isoenzyme pattern &
DNA peptide mapping).
Monoclonal antibody specificity.

7. Factors governing Leishmanial infection:
1- Vector governs geographical distribution.
2- Parasite governs tissue involved.
3- Host governs course of infection.
Innate & acquired immune response influence tissue damage & intra cellular killing.

8. Route of infection / infectivity:
Bite of infected sand fly, lutzomia Congenital
Transfusion
Sharing needles.

9. Splenomegaly and hepatomegaly
 Disseminated coetaneous leishmaniasis.
Splenomegaly and hepatomegaly
are hallmarks of classic visceral leishmaniasis.

10. Immunology: Cinderella of Tropical Medicine
Paradigm for studies of T cells
subsets & cytokines govern intra
cellular resistance of pathogen.
INF TH1 & NK cells Resistance
IL naive T cells TH TH1&NK cells INF-8
IL TH susceptibility, progression of disease
IL associated with pathology
TH macrophage activation for promastigote killing

11. Pathogenesis / Course of visceral Leishmaniasis:
Inoculation
Weeks / months
Insignificant local
lesion
amastigote
promastigote
killed
type
Healing + local immunity
size
virulence
No local / visceral lesion
Parasitic
dissimination
Well contained
unrestained
Asymptomatic visceral
(Scanty liver granuloma)
Death if not treated

12. Role of serum Parasitemia & dissemination Role of CMI
Great lyses in - vitro
Genetics HLA
low responders
High responders
Single gene linked to H2
nutrition
virulence
Symptomatic
Asymptomatic +
Focal lesion +
Liver granuloma
amount
HIV
treated
Not treated
pyrexia
Recovery
Death
emaciation
Secondary infection
Skim test ++
Relapse: rare
PKDL 6%
Altered tropism parasite+ skim test+
Antigen alteration

13. Mechanism of anemia in Kala Azar:
Ineffective erythropoesis
RBC life span
splenomegaly
Antigens
(coombs+ve in 30%)
Anaemia
plasma volume
Complement activated on RBCs
immunoconglutinins
iron absorption
TIBC
serum iron

14. In Symptomatic Cases:
Immune exhaustion (compared to African trypanosomiasis)
Emaciation
Secondary infection
Pyrexia (Similar to that of endotoxin)
Hepato splenomegaly
Decreased T cells
Increased B cells
Increase IgG, IgM, (Formal gel test)
Immune complex disease
Rheumatoid factor positive in 70%
Anemia of chronic infection

15. Pathogenesis / Course of Cutaneous Leishmaniasis
104 x 4
inculation
dose
Cutanous
lesion
Size of inoculum
Amount of replication
3/52
Non
healing
Non ulcerating
ulcerating
Degree of deficiency
Healing
Repair
Cell recruitment
Lymphocyte population
Solid immunity
recideva
Lympho toxin
Tissue damage
Cytotoxic cells
Macrophage enzymes

16. Rural: multiple, parasite +
Incubation period: inversely proportional to size of inoculums
Rural: multiple, parasite +
Urban: single, longer IP, parasite +
3 – 4 months later leishmanin test +ve

17. Pathogenesis / Summery
Conclusion from clinical studios:
Parasite determines the site:
VISCERAL
Asymptomatic
Fatal course
High responders
Low responders
Size of inoculum
?Genetics

18. Ineffective response Diffuse coetaneous Oriental sore
Parasite +++
No ulceration
No healing
Lymphocytes +
Oriental
sore
normal response
Wet or dry
Depends on
Property of the
Parasite
Parasites +
Lymphocytes ++
Macrophages ++
Ulceration & healing
Compared to Lepromatus Leprosy

19. CHICLEROS
ULCER &
Espundia
Antigen
ulteration
PKDL
Exajurated
response
Mucosal
Espondia
Exaggerated
Parasites –
Lymphocytes ++
Macrophages ++
Ulceration
No healing
Compared to tuberculoid Leprosy
Tuberculoid Lesion
Parasite +
Massive tissue destruction
Uttered tropism
Parasites +
Skin test +
History: any point in sputum of coetaneous Leishmaniasis

21. +++
+++
Bacilli in
billions
Resistance
number ++ ++
Lepromintest
Liehmanin test
Bacilli + + LL
DCL TT
Chicleros BT BB BL
Similarity in clinical spectrum between leishmaniasis & Leprosy

22. CLINICAL
IP for visceral leishmaniasis is variable but typically ranges from 2 to 8 months.
Sub acute or chronic course, but in some cases the onset is more abrupt.
Fever, malaise, anorexia, weight loss, and enlargement of the abdomen.
Fever, intermittent, remittent with twice-daily temperature spikes to 38 to 40° C, or less commonly, continuous.
It is generally well tolerated.
Of note, visceral leishmaniasis has developed in former residents of endemic areas who became immunocompromised years after leaving the areas.

23. Wasting can be pronounced in chronic infection. Hyper pigmentation.
Splenomegaly and hepatomegaly are hallmarks of classic visceral leishmaniasis.
The spleen is firm and nontender and frequently becomes massively enlarged.
Lymphadenopathy
Wasting can be pronounced in chronic infection.
Hyper pigmentation.
Jaundice is occasionally present.
Later patients may experience epistaxis,
gingival bleeding, and petechiae.
Edema and ascites as a result of hypoalbuminemia.

24. laboratory examination
anemia,
thrombocytopenia, neutropenia, and
Hyper gammaglobulinemia are common.
The anemia usually normocytic and normochromic unless complicated by blood loss.
The white blood cell count may be as low as 1000/ mL; eosinopenia is common.
Hemophagocytosis observed in bone marrow specimens.
ESR and CRP are elevated.

25. Glomerulonephritis may develop, but renal failure is rare.
Levels of gamma globulin are markedly increased, at times in the range of 9 to 10 g/dL, as a consequence of polyclonal B-cell activation.
Circulating immune complexes, autoantibodies, and rheumatoid factors are present in many patients.
Glomerulonephritis may develop, but renal failure is rare.
Liver enzyme and bilirubin levels are elevated in some.
Hypertriglyceridemia and hypofibrinogenemia have also been reported.

26. Bone marrow aspirate smear: visceral leishmaniasis

27. Viscerotropic Leishmaniasis
In the L. tropica–related “viscerotropic” syndrome observed in American military personnel during Operation
Desert Storm, symptoms included chronic low-grade fever, malaise, fatigue, and in some instances, diarrhea.
The troops did not experience massive splenomegaly or the progressive wasting associated with classic visceral leishmaniasis.

28. Post kala- azar dermal leishmaniasis
Is a coetaneous condition characterized by a macular, depigmented eruption mainly on the face, arms, and upper part of the trunk.
It occurs years after the successful treatment of 
visceral leishmaniasis.
The facial lesions progressing to papules and nodules resembling those of lepromatous leprosy.

30. leishmaniasis reci´divans
A prolonged, relapsing form of coetaneous leishmaniasis resembling tuberculosis of the skin.
It is an evolving form of coetaneous leishmaniasis which clinically presents as a spreading of the initial nodule, leading to a plaque formation simulating discoid lupus erythematosus.
A clinical course of leishmania
recidivans is probably related to
changes in cell-mediated
immunity leading to localized or
diffuse lesions.

34. Differential Diagnosis of Leishmaniasis
Cutaneous leishmaniasis
Bacterial skin infections
Blastomycosis
Cutaneous anthrax
Eczema
Fungal skin infections
Leprosy
Mycobacterium marinum
Myiasis
Sarcoidosis
Skin cancer
Sporotrichosis
Syphilis
Tuberculosis
Yaws
Verrucous lesions
Mucosal leishmaniasis
Behçet's syndrome
Discoid lupus erythematosus
Histoplasmosis
Lethal midline granuloma
Neoplasms
Paracoccidioidomycosis
Rhinoscleroma
Sarcoidosis
Syphilis
Tuberculosis
Wegener's granulomatosis
Yaws

35. Reasons to Treat Cutaneous Leishmaniasis
Cosmetically unacceptable lesions
Chronic lesions
Large lesions
Lesions in immune suppressed patients
Lesions over joints
Mucosal disease
Multiple lesions
Nodular lymphangitis
Worsening lesions

36. Treatment of Cutaneous Leishmaniasis
Pentavalent antimony
Meglumine antimoniate (Glucantime) and sodium stibogluconate (Pentostam); cure rate 94 percent; eliminated by kidneys
Dosage: 20 mg per kg per day for 20 days
Stibogluconate supplied as 100 mg Sb per mL light-sensitive solution
Calculated dose (12 to 20 mL for adults) is diluted in 50 mL of 5 percent dextrose in distilled water, infused intravenously over 10 to 15 minutes
Amphotericin B (Fungizone)
Reserved for antimony failures
Dosage: 0.5 to 1.0 mg per kg every other day for up to eight weeks; total dosage is 1.5 to 2 g for the treatment period

37. Pentamidine isethionate (Pentam 300)
Dosage: 2 mg per kg intramuscularly every other day for seven days
Toxic effects: damage to pancreas,
kidney, or bone marrow may be irreversible
May induce diabetes mellitus
Others
Topical paromomycin is effective with L. major and L. mexicana. It can be combined with antimonials to reduce the number of injections.
Oral antifungals have demonstrated conflicting results, although some good results have been achieved with L. mexicana19 and L. major.18
Allopurinol (Zyloprim) incorporates into parasite RNA with lethal effect. Studies are conflicting, and it is not recommended, although there is synergistic activity with antimonials.11-14
Heat15-16 and cryotherapy17 show good results in uncontrolled trials.
Excision is not recommended because of the high risk of local relapse and disfiguration.